Regulation of Inflammasome Function by the Ubiquitin System

"Inflammasomes are intracellular multimeric protein complexes that act as immunological sensors detecting a wide range of microbial- and host-derived signals and, in their active form, promote cytokine release and inflammatory cell death. They have emerged as key mediators of inflammation in health and disease and high-value targets for therapeutic intervention, however, we are far from a complete understanding of inflammasome functional regulation. The activity of inflammasomes has been reported to depend on various post translational modifications (PTMs) including ubiquitination.
We argue that the lack of evaluation of ubiquitin involvement in inflammasome regulation is in part due the lack of quantitative tools to assess the state of these systems. We have developed sensitive quantitative mass spectrometry (MS) approaches that will be adapted to address this question. Specifically, we have pioneered advanced mass spectrometry methods substantially improving performance over standard MS methods in terms of sensitivity, speed, and robustness of quantification. These tools will allow us to characterize molecular details of ubiquitination in inflammasome regulation leading to functional hypotheses that we will test using phenotypic assays in therapeutically relevant human cell systems.
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